tbuckley/cabot-search huggingface dataset:
First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors
Authors: Omid Hamid, Alberto A Chiappori, John A Thompson, Toshihiko Doi, Siwen Hu-Lieskovan, Ferry A L M Eskens, Willeke Ros, Adi Diab, Jean-Philippe Spano, Naiyer A Rizvi, Jeffrey S Wasser, Eric Angevin, Patrick A Ott, Alison Forgie, Wenjing Yang, Cen Guo, Jeffrey Chou, Anthony B El-Khoueiry
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors. Methods Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1–3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every 4 weeks (Q4W)) intravenously. Dose-expansion: patients with melanoma (n=10) and NSCLC (n=20) who progressed on prior anti-programmed death receptor 1/programmed death ligand-1 and/or anti-cytotoxic T-lymphocyte-associated antigen 4 (melanoma) received ivuxolimab 30 mg Q2W intravenously plus utomilumab 20 mg Q4W intravenously. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and immune-related RECIST (irRECIST). Paired tumor biopsies and whole blood were collected to assess pharmacodynamic effects and immunophenotyping. Whole blood samples were collected longitudinally for immunophenotyping. Results Dose-escalation: 57 patients were enrolled; 2 (3.5%) patients with melanoma (0.3 mg/kg+20 mg and 0.3 mg/kg+100 mg) achieved partial response (PR), 18 (31.6%) patients achieved stable disease (SD); the disease control rate (DCR) was 35.1% across all dose levels. Dose-expansion: 30 patients were enrolled; 1 patient with NSCLC achieved PR lasting &gt;77 weeks. Seven of 10 patients with melanoma (70%) and 7 of 20 patients with NSCLC (35%) achieved SD: median (range) duration of SD was 18.9 (13.9–49.0) weeks for the melanoma cohort versus 24.1 (14.3–77.9+) weeks for the NSCLC cohort; DCR (NSCLC) was 40%. Grade 3–4 treatment-emergent AEs were reported in 28 (49.1%) patients versus 11 (36.7%) patients in dose-escalation and dose-expansion, respectively. There were no grade 5 AEs deemed attributable to treatment. Ivuxolimab area under the concentration–time curve increased in a dose-dependent manner at 0.3–3 mg/kg doses. Conclusions Ivuxolimab+utomilumab was found to be well tolerated and demonstrated preliminary antitumor activity in selected groups of patients. Trial registration number NCT02315066 .
Metabolic features of innate lymphoid cells
Authors: Huiyang Yu, Nicolas Jacquelot, Gabrielle T. Belz
Journal: The Journal of Experimental Medicine (2022)

Innate and adaptive immune cells are found in distinct tissue niches where they orchestrate immune responses. This requires intrinsic and temporal metabolic adaptability to coordinately activate the immune response cascade. Dysregulation of this program is a key feature of immunosuppression. Direct or indirect metabolic immune cell reprogramming may offer new approaches to modulate immune cells behavior for therapy to overcome dysregulation. In this review, we explored how metabolism regulates lymphocytes beyond the classical T cell subsets. We focus on the innate lymphoid cell (ILC) family, highlighting the distinct metabolic characteristics of these cells, the impact of environmental factors, and the receptors that could alter immune cell functions through manipulation of metabolic pathways to potentially prevent or treat various diseases.
Prognostic and therapeutic significance of microbial cell-free DNA in plasma of people with acute decompensation of cirrhosis
Authors: Beiling Li, Changze Hong, Zhiping Fan, Shumin Cai, Qinjun He, Xiaoqin Lan, Qintao Lai, Yali Ji, Wenfan Luo, Junying Li, Xiao Cheng, Miaoxia Liu, Yixiu Gu, Guanting Lu, Shaochuan Li, Yali Wang, Xing Weng, Xiaoyun Niu, Qifa Liu, Rajiv Jalan, Jinjun Chen
Journal: Journal of Hepatology (2022)

Although the effect of bacterial infection on cirrhosis has been well-described, the effect of non-hepatotropic virus (NHV) infection is unknown. This study evaluated the genome fragments of circulating microorganisms using metagenomic next-generation sequencing (mNGS) in individuals with acute decompensation (AD) of cirrhosis, focusing on NHVs, and related the findings to clinical outcomes.Plasma mNGS was performed in 129 individuals with AD of cirrhosis in the study cohort. Ten healthy volunteers and 20, 39, and 81 individuals with stable cirrhosis, severe sepsis and hematological malignancies, respectively, were enrolled as controls. Validation assays for human cytomegalovirus (CMV) reactivation were performed in a validation cohort (n = 58) and exploratory treatment was instituted.In the study cohort, 188 microorganisms were detected in 74.4% (96/129) of patients, including viruses (58.0%), bacteria (34.1%), fungi (7.4%) and chlamydia (0.5%). A NHV signature was identified in individuals with AD, and CMV was the most frequent NHV, which correlated with the clinical effect of empirical antibiotic treatment, progression to acute-on-chronic liver failure, and 90-day mortality. The NHV signature in individuals with acute-on-chronic liver failure was similar to that in those with sepsis and hematological malignancies. CMV was detected in 24.1% (14/58) of patients in the validation cohort. Of the 14 cases with detectable CMV by mNGS, nine were further validated by real-time PCR or pp65 antigenemia testing. Three patients with CMV reactivation received ganciclovir therapy in an exploratory manner and experienced clinical resolutions.The results of this study suggest that NHVs may play a pathogenic role in complicating the course of AD. Further validation is needed to define whether this should be incorporated into the routine management of individuals with AD of cirrhosis.A non-hepatotropic virus (NHV) signature, which was similar to that in individuals with sepsis and hematological malignancies, was identified in individuals with acute decompensation of cirrhosis. The detected viral signature had clinical correlates, including clinical efficacy of empirical antibiotic treatment, progression to acute-on-chronic liver failure and short-term mortality. Cytomegalovirus reactivation, which is treatable, may adversely affect clinical outcomes in some individuals with decompensated cirrhosis. Routine screening for NHVs, especially cytomegalovirus, may be useful for the management of individuals with acute decompensation of cirrhosis.
WITHDRAWN:Prussian blue nanozymes coated with pluronic attenuate inflammatory osteoarthritis by blocking c-Jun N-terminal kinase phosphorylation
Authors: Chanmi Cho, Hyeryeon Oh, Jin Sil Lee, Li-Jung Kang, Eun-Jeong Oh, Yiseul Hwang, Seok Jung Kim, Yong-Soo Bae, Eun-Jeong Kim, Ho Chul Kang, Won Il Choi, Siyoung Yang
Journal: Biomaterials (2022)
Immunological and virological findings in a patient with exceptional post-treatment control: a case report
Authors: Núria Climent, Juan Ambrosioni, Tània González, Cristina Xufré, Maria Casadellà, Marc Noguera-Julian, Roger Paredes, Montserrat Plana, Judith Grau-Expósito, Josep Mallolas, José Alcamí, Sonsoles Sánchez-Palomino, José M Miró, David Nicolás, Cristina Xufré, Carmen Hurtado, Cristina Rovira, Omar Sued, Mercé Brunet, María López-Diéguez, Christian Manzardo, Fernando Agüero, Montserrat Tuset, Alberto C Guardo, Maria A. Marcos, María del Mar Mosquera, M. Ángeles Muñoz-Fernández, Miguel Caballero, Carmen Ligero, Emma Fernández, M. Ángeles Marcos, José M Gatell, Elisa de Lazzari, Teresa Gallart, Ana Fernandez-Tenreiro, Begoña Gomez, Leire Berrocal, David Nicolás, Cristina Xufré, Carmen Hurtado, Cristina Rovira, Omar Sued, Mercé Brunet, María López-Diéguez, Christian Manzardo, Fernando Agüero, Montserrat Tuset, Alberto C Guardo, Maria A. Marcos, María del Mar Mosquera, M. Ángeles Muñoz-Fernández, Miguel Caballero, Carmen Ligero, Emma Fernández, M. Ángeles Marcos, José M Gatell, Elisa de Lazzari, Teresa Gallart, Ana Fernandez-Tenreiro, Begoña Gomez, Leire Berrocal
Journal: The Lancet HIV (2022)
Tuning pro-survival effects of human induced pluripotent stem cell-derived exosomes using elastin-like polypeptides
Authors: Chen-Hung Lee, Daniel Hunt, Julien George Roth, Ching-Chi Chiu, Riley A. Suhar, Bauer L. LeSavage, Alexis Jane Seymour, Chris Lindsay, Brad A. Krajina, Yi-Tung Chen, Kuo-Hsuan Chang, I-Chang Hsieh, Pao-Hsien Chu, Ming-Shien Wen, Sarah C. Heilshorn
Journal: Biomaterials (2022)
Physical activity and exercise for cancer-related cognitive impairment among individuals affected by childhood cancer: a systematic review and meta-analysis
Authors: Joshua D K Bernal, Francesco Recchia, Danny J Yu, Daniel Y Fong, Stephen H S Wong, Pak-Kwong Chung, Derwin K C Chan, Catherine M Capio, Clare C W Yu, Sam W S Wong, Cindy H P Sit, Ya-Jun Chen, Walter R Thompson, Parco M Siu
Journal: The Lancet Child & Adolescent Health (2022)
Re: ‘the unique COVID-19 presentation of patients with B cell depletion’ by Belkin et al.
Authors: Elena Múñez-Rubio, Jorge Calderón-Parra, Ana Fernández-Cruz, Víctor Moreno-Torres, Silvia Blanco-Alonso, Antonio Ramos-Martínez
Journal: Clinical Microbiology and Infection (2022)
Heliangin acts as a covalent ligand of RPS2 that disrupts pre-rRNA metabolic processes in NPM1-mutated acute myeloid leukemia
Authors: Yin Feng, Yefan Han, Anni Hu, Yi Qu, Yili Hu, Hao Wu, Xinzhi Wang, Li He
Journal: Acta Pharmaceutica Sinica B (2022)

Although NPM1 mutations are frequently found in acute myeloid leukemia patients, therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy. Here we demonstrated that heliangin, a natural sesquiterpene lactone, exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells, with no apparent toxicity to normal hematogenous cells, by inhibiting their proliferation, inducing apoptosis, causing cell cycle arrest, and promoting differentiation. In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2 (RPS2) is the main target of heliangin in treating NPM1 mutant AML. Upon covalent binding to the C222 site of RPS2, the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes, leading to nucleolar stress, which in turn regulates the ribosomal proteins-MDM2-p53 pathway and stabilizes p53. Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation, leading to a poor prognosis. We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target. Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients, especially those with NPM1 mutations.
LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial
Authors: Shweta Urva, Tamer Coskun, Mei Teng Loh, Yu Du, Melissa K Thomas, Sirel Gurbuz, Axel Haupt, Charles T Benson, Martha Hernandez-Illas, David A D'Alessio, Zvonko Milicevic
Journal: The Lancet (2022)
Chronic remote ischaemic conditioning in patients with symptomatic intracranial atherosclerotic stenosis (the RICA trial): a multicentre, randomised, double-blind sham-controlled trial in China
Authors: Chengbei Hou, Jing Lan, Yinan Lin, Haiqing Song, Yuan Wang, Wenbo Zhao, Sijie Li, Ran Meng, Junwei Hao, Yuchuan Ding, Marc I Chimowitz, Marc Fisher, David C Hess, David S Liebeskind, Derek J Hausenloy, Jie Huang, Zhenguang Li, Xiujie Han, Jinbo Yang, Jin Zhou, Peimin Chen, Xinchen Zhu, Peilin Hu, Hongbo Pang, Wenwu Chen, Huisheng Chen, Guozhong Li, Dingbo Tao, Wei Yue, Zongen Gao, Xunming Ji
Journal: The Lancet Neurology (2022)
Patterns of Neural Functional Connectivity in Infants at Familial Risk of Developmental Dyslexia
Authors: Xi Yu, Silvina Ferradal, Jade Dunstan, Clarisa Carruthers, Joseph Sanfilippo, Jennifer Zuk, Lilla Zöllei, Borjan Gagoski, Yangming Ou, P. Ellen Grant, Nadine Gaab
Journal: JAMA Network Open (2022)

Developmental dyslexia is a heritable learning disability affecting 7% to 10% of the general population and can have detrimental impacts on mental health and vocational potential. Individuals with dyslexia show altered functional organization of the language and reading neural networks; however, it remains unknown how early in life these neural network alterations might emerge.To determine whether the early emergence of large-scale neural functional connectivity (FC) underlying long-term language and reading development is altered in infants with a familial history of dyslexia (FHD).This cohort study included infants recruited at Boston Children's Hospital between May 2011 and February 2019. Participants underwent structural and resting-state functional magnetic resonance imaging in the Department of Radiology at Boston Children's Hospital. Infants with FHD were matched with infants without FHD based on age and sex. Data were analyzed from April 2019 to June 2021.FHD was defined as having at least 1 first-degree relative with a dyslexia diagnosis or documented reading difficulties.Whole-brain FC patterns associated with 20 predefined cerebral regions important for long-term language and reading development were computed for each infant. Multivariate pattern analyses were applied to identify specific FC patterns that differentiated between infants with vs without FHD. For classification performance estimates, 99% CIs were calculated as the classification accuracy minus chance level.A total of 98 infants (mean [SD] age, 8.5 [2.3] months; 51 [52.0%] girls) were analyzed, including 35 infants with FHD and 63 infants without FHD. Multivariate pattern analyses identified distinct FC patterns between infants with vs without FHD in the left fusiform gyrus (classification accuracy, 0.55 [99% CI, 0.046-0.062]; corrected P < .001; Cohen d = 0.76). Connections linking left fusiform gyrus to regions in the frontal and parietal language and attention networks were among the paths with the highest contributions to the classification performance.These findings suggest that on the group level, FHD was associated with an early onset of atypical FC of regions important for subsequent word form recognition during reading acquisition. Longitudinal studies linking the atypical functional network and school-age reading abilities will be essential to further elucidate the ontogenetic mechanisms underlying the development of dyslexia.
Prevalence and Correlates of Long COVID Symptoms Among US Adults
Authors: Roy H. Perlis, Mauricio Santillana, Katherine Ognyanova, Alauna Safarpour, Kristin Lunz Trujillo, Matthew D. Simonson, Jon Green, Alexi Quintana, James Druckman, Matthew A. Baum, David Lazer
Journal: JAMA Network Open (2022)

Importance Persistence of COVID-19 symptoms beyond 2 months, or long COVID, is increasingly recognized as a common sequela of acute infection. Objectives To estimate the prevalence of and sociodemographic factors associated with long COVID and to identify whether the predominant variant at the time of infection and prior vaccination status are associated with differential risk. Design, Setting, and Participants This cross-sectional study comprised 8 waves of a nonprobability internet survey conducted between February 5, 2021, and July 6, 2022, among individuals aged 18 years or older, inclusive of all 50 states and the District of Columbia. Main Outcomes and Measures Long COVID, defined as reporting continued COVID-19 symptoms beyond 2 months after the initial month of symptoms, among individuals with self-reported positive results of a polymerase chain reaction test or antigen test. Results The 16 091 survey respondents reporting test-confirmed COVID-19 illness at least 2 months prior had a mean age of 40.5 (15.2) years; 10 075 (62.6%) were women, and 6016 (37.4%) were men; 817 (5.1%) were Asian, 1826 (11.3%) were Black, 1546 (9.6%) were Hispanic, and 11 425 (71.0%) were White. From this cohort, 2359 individuals (14.7%) reported continued COVID-19 symptoms more than 2 months after acute illness. Reweighted to reflect national sociodemographic distributions, these individuals represented 13.9% of those who had tested positive for COVID-19, or 1.7% of US adults. In logistic regression models, older age per decade above 40 years (adjusted odds ratio [OR], 1.15; 95% CI, 1.12-1.19) and female gender (adjusted OR, 1.91; 95% CI, 1.73-2.13) were associated with greater risk of persistence of long COVID; individuals with a graduate education vs high school or less (adjusted OR, 0.67; 95% CI, 0.56-0.79) and urban vs rural residence (adjusted OR, 0.74; 95% CI, 0.64-0.86) were less likely to report persistence of long COVID. Compared with ancestral COVID-19, infection during periods when the Epsilon variant (OR, 0.81; 95% CI, 0.69-0.95) or the Omicron variant (OR, 0.77; 95% CI, 0.64-0.92) predominated in the US was associated with diminished likelihood of long COVID. Completion of the primary vaccine series prior to acute illness was associated with diminished risk for long COVID (OR, 0.72; 95% CI, 0.60-0.86). Conclusions and Relevance This study suggests that long COVID is prevalent and associated with female gender and older age, while risk may be diminished by completion of primary vaccination series prior to infection.
Aging-suppressor Klotho: Prospects in diagnostics and therapeutics
Authors: Carmela R. Abraham, Anne Li
Journal: Ageing Research Reviews (2022)

The protein Klotho (KL) was first discovered in KL-deficient mice, which developed a syndrome similar to premature aging in humans. Since then, KL has been implicated in multiple molecular signaling pathways and diseases. KL has been shown to have anti-aging, healthspan and lifespan extending, cognitive enhancing, anti-oxidative, anti-inflammatory, and anti-tumor properties. KL levels decrease with age and in many diseases. Therefore, it has been of great interest to develop a KL-boosting or restoring drug, or to supplement endogenous Klotho with exogenous Klotho genetic material or recombinant Klotho protein, and to use KL levels in the body as a marker for the efficacy of such drugs and as a biomarker for the diagnosis and management of diseases. The goal of this study was to provide a comprehensive review of KL levels across age groups in individuals who are healthy or have certain health conditions, using four sources: blood, cerebrospinal fluid, urine, and whole biopsy/necropsy tissue. By doing so, baseline KL levels can be identified across the lifespan, in the absence or presence of disease. In turn, these findings can be used to guide the development of future KL-based therapeutics and biomarkers, which will heavily rely on an individual's baseline KL range to be efficacious. A total of 65 studies were collected primarily using the PubMed database. Research articles that were published up to April 2022 were included. Statistical analysis was conducted using RStudio. Mean and median blood KL levels in healthy individuals, mean blood KL levels in individuals with renal conditions, and mean blood KL levels in individuals with metabolic or endocrine conditions were shown to decrease with age. Similarly, CSF KL levels in patients with AD also declined compared with age-matched controls. The present study confirms the trend that KL levels in blood decrease with age in humans, among those who are healthy, and even further among those with renal and endocrine/metabolic illnesses. Further, by drawing this trend from multiple published works, we were able to provide a general idea of baseline KL ranges, specifically in blood in these populations. These data add to the current knowledge on normal KL levels in the body and how they change with time and in disease, and can potentially support efforts to create KL-based treatments and screening tools to better manage aging, renal, and metabolic/endocrine diseases.
Treatment of HCC with claudin-1-specific antibodies suppresses carcinogenic signaling and reprograms the tumor microenvironment
Authors: Natascha Roehlen, Marion Muller, Zeina Nehme, Emilie Crouchet, Frank Jühling, Fabio Del Zompo, Sara Cherradi, Francois H.T. Duong, Nuno Almeida, Antonio Saviano, Mirian Fernández-Vaquero, Tobias Riedl, Houssein El Saghire, Sarah C. Durand, Clara Ponsolles, Marine A. Oudot, Romain Martin, Nicolas Brignon, Emanuele Felli, Patrick Pessaux, Antonin Lallement, Irwin Davidson, Simonetta Bandiera, Christine Thumann, Patrice Marchand, Solange Moll, Brandon Nicolay, Nabeel Bardeesy, Yujin Hoshida, Mathias Heikenwälder, Roberto Iacone, Alberto Toso, Markus Meyer, Greg Elson, Tamas Schweighoffer, Geoffrey Teixeira, Mirjam B. Zeisel, Patrice Laquerriere, Joachim Lupberger, Catherine Schuster, Laurent Mailly, Thomas F. Baumert
Journal: Journal of Hepatology (2022)
Mass drug administration of azithromycin: an analysis
Authors: Rebecca Kahn, Nir Eyal, Samba O. Sow, Marc Lipsitch
Journal: Clinical Microbiology and Infection (2022)

WHO recommends mass drug administration (MDA) of the antibiotic azithromycin for children aged 1-11 months in areas with high rates of infant and child mortality. Notwithstanding the substantial potential benefits of lowering childhood mortality, MDA raises understandable concerns about exacerbating antibiotic resistance.In this study, we aimed to evaluate the use of MDA using both quantitative and ethical considerations.We performed a series of literature searches between July 2019 and June 2022.We first compared MDA with other uses of antibiotics using the standard metric of 'number needed to treat', and five additional criteria: (1) other widely accepted uses of anti-infectives (2) absolute use (i.e. total number), of antibiotics, (3) risk-benefit trade-off, (4) availability of short-term alternatives, and (5) the precedent for implementing similar interventions. We found that MDA falls well within a justifiable range when compared with widely accepted uses of antibiotics in terms of the number needed to treat. The other five criteria we considered provided further support for the use of MDA to prevent childhood mortality.Although better data on antibiotic use and resistance are needed, efforts to reduce antibiotic use and resistance should not start with halting MDA of azithromycin in the areas with the highest rates of childhood mortality. Improving data to inform this decision is critical. However, on the basis of the best evidence available, we believe that concerns regarding resistance should not thwart MDA; instead, MDA should be accompanied by robust plans to monitor its efficacy and changes in resistance levels. Similar considerations could be included in a framework for evaluating the benefits of antibiotics against the risk of resistance in other contexts.
An MDM2 degrader for treatment of acute leukemias
Authors: Bridget K. Marcellino, Xiaobao Yang, H. Ümit Kaniskan, Claudia Brady, He Chen, Karie Chen, Xing Qiu, Cara Clementelli, Lauren Herschbein, Zhijun Li, Sebastian Elghaity-Beckley, Joann Arandela, Brianna Kelly, Ronald Hoffman, Jing Liu, Yue Xiong, Jian Jin, Alan H. Shih
Journal: Leukemia (2022)